Pregnancy malaria (PM) caused by Plasmodium falciparum contributes to about 150,000 child and 10,000 mother deaths annually in malaria endemic regions. Infant mortality in PM is largely due to low birth weight (LBW); however PM also causes stillbirth and abortion. LBW is associated with parasitized erythrocyte (PE) sequestration and consequent inflammation in the placenta; however, the precise molecular details of maternal- fetal interactions in PM and placental changes leading to fetal growth restriction/LBW are still poorly understood. The long-term purpose of this project is to clarify molecular details of these processes. This project will focus on the role of megalin-associated multi-ligand scavenging and signal transduction system, which is highly expressed in placental syncytiotrophoblast. This system may mediate and regulate a substantial amount of maternofetal exchange and homeostasis of vitamins, lipids, hormones, Ca2+, matrix proteases and inhibitors, and other carrier proteins, including receptor cubilin and its ligands. The megalin system plays an extremely important role in embryonic development and murine knock-out of megalin or its intracellular adaptor protein Dab2 leads to 98% perinatal mortality. We hypothesize that PM disturbs megalin function/expression/distribution in syncytiotrophoblast which, in turn, may contribute significantly to the placental pathology due to the high importance of the molecules, handled by this receptor, for normal fetal growth/development. Our preliminary results strongly support this hypothesis. To understand the role of the megalin system in maternal-fetal interactions and in placental pathology during PM we suggest the following Specific Aims: 1) Analyze abundance of megalin system proteins in placental sections from malaria endemic regions and relate it to PM pathology using antibodies against megalin, cubilin, and Dab2 and immunofluorescence microscopy assay (IFA), as well as reverse transcription-PCR approach; 2) Study the effect of parasitized erythrocyte (PE) adhesion to the villous cytotrophoblast BeWo cells on megalin system protein expression, trafficking, ligand transfer, and signal transduction. We will use real time fluorescence microscopy, IFA, RT-PCR, biochemical and cell biological approaches. We will also test whether the addition of human macrophages to PE bound on the surface of BeWo cells may affect these processes thus modeling the initial steps of the innate immune response before the development of an adaptive response in primigravida women, most susceptible to PM pathology. These experiments will test our hypothesis about potential role of proteins of the megalin transporting/signaling system in the placental transfer of nutrients and regulatory molecules, and association of their abundance/distribution with PM and/or with LBW. This, in turn, will create a basis for future expanded studies of maternofetal exchange, pathological changes, and mechanisms of fetal growth restriction/LBW related to megalin functions in PM, a substantial contributor to infant mortality and morbidity in malaria endemic regions.